Scientists discover way to repair synapses damaged by Alzheimer’s

Slowing the progression of dementia is one thing, but how do we repair the damage inflicted? Buck scientists may have the answer…

Although there has been cautious optimism of late, with some newly-approved drugs for Alzheimer’s showing some promise for slowing the debilitating neurodegenerative disease, there has been less progress in repairing the damage and regaining memory.

Longevity.Technology: Alzheimer’s research took a hit yesterday, when Biogen announced it was halting sales and development of its Alzheimer’s drug Aduhelm. However, as one door closes, another one often opens, and a paper published today in The Journal of Clinical Investigation details how scientists at The Buck Institute for Research on Aging have defined a mechanism for plasticity repair in vulnerable neurons by using part of a protein.

Senior author of the study, Buck Assistant Professor Tara Tracy, PhD, says that Alzheimer’s research needs more treatment options targeted to restore memory.

Since most current research on potential treatments for Alzheimer’s focuses on reducing the toxic proteins, such as tau and amyloid beta, that accumulate in the brain as the disease progresses, the research team swerved this approach, focusing their attention on exploring an alternative, instead.

“Rather than trying to reduce toxic proteins in the brain, we are trying to reverse the damage caused by Alzheimer’s disease to restore memory,” says Tracy.

The mechanism identified depends on a protein which is found in the kidney and the brain, and called (wait for it) KIBRA. In the brain, KIBRA is primarily localized at the synapses, which are the connections between neurons that allow memories to be formed and recalled. Research has shown that KIBRA is required for synapses to form memories, and Tracy’s team has found that brains with Alzheimer’s disease are deficient in KIBRA [1].

Researchers at the Buck Institute identified recovery of the functional plasticity at synapses on neurons despite tau-induced toxicity in the brain. Image credit: Larissa Brown.

“We wondered how the lower levels of KIBRA affected signaling at the synapse, and whether understanding that mechanism better could yield some insight into how to repair the synapses damaged during the course of Alzheimer’s disease,” said Buck Staff Scientist Grant Kauwe, PhD, co-first author of the study. “What we identified is a mechanism that could be targeted to repair synaptic function, and we are now trying to develop a therapy based on this work.”

The team first measured the levels of KIBRA in the cerebrospinal fluid (CSF)of humans. They found that higher levels of KIBRA in the CFS, but lower levels in the brain, corresponded to the severity of dementia [1].

“We also found this amazing correlation between increased tau levels and increased KIBRA levels in the cerebrospinal fluid,” said Tracy. “It was very surprising how strong the relationship was, which really points to the role of KIBRA being affected by tau in the brain.”

To determine just how KIBRA affects synapses, the team created a shortened functional version of the KIBRA protein. In laboratory mice that have a condition mimicking human Alzheimer’s disease, they found that this protein can reverse the memory impairment associated with this type of dementia. They found that KIBRA rescues mechanisms that promote the resilience of synapses.

Image shows neurons in the hippocampus immunostained for NeuN (red) with markers for dendrites (green) and nuclei (blue). Image credit: Kristeen Pareja-Navarro.

Now the Buck team is further exploring this phenomenon, in the hope that KIBRA could be used as a biomarker of synaptic dysfunction and cognitive decline; this would mean Kibra could prove useful for diagnosis, treatment planning, and tracking disease progression and response to therapy.

“Interestingly, KIBRA restored synaptic function and memory in mice, despite not fixing the problem of toxic tau protein accumulation,” said Kristeen Pareja-Navarro, co-first author of the study. “Our work supports the possibility that KIBRA could be used as a therapy to improve memory after the onset of memory loss, even though the toxic protein that caused the damage remains.”

Treating Alzheimer’s is likely to need combination therapy that targeting the different pathogenic pathways in the disease in a synergistic way. A KIBRA therapy to repair synapses would prove to be a valuable addition.

“Reducing toxic proteins is of course important, but repairing synapses and improving their function is another critical factor that could help,” said Tracy. “That’s how I see this making the biggest impact in the future.”

[1] https://www.jci.org/articles/view/169064

Photographs courtesy of The Buck Institute / Larissa Brown / Kristeen Pareja-Navarro